Heat shock proteins (hsps) are highly conserved constitutive and induced proteins found in cells from bacteria to human beings. S. Lindquist, Ann. Rev. Biochem 55, 1151 (1986). The constitutive hsps are critical to many diverse cellular functions. The most ubiquitous and best studied hsp family, the group of hsp's with molecular weights close to 70,000 daltons (hsp70), has been shown to assist in translocation of proteins into the endoplasmic reticulum and mitochondria, R. Deshais et al., Nature 332,800 (1988), W. Chirico et al., Nature 332, 805 (1988). Hsp 70 also has been implicated as the clathrin-uncoating ATPase, T. Chapell et al., Cell 45, 3 (1986). Potential structural functions of other hsps include: linking the actin cytoskeleton to the plasmalemma, S. Koyasu et al., Proc. Natl. Acad. Sci. USA 83, 8054 (1986); specifically binding saturated fatty acids, P. Guidon and L. Hightower, Biochemistry 25, 3231 (1986); P. Guidon and L. Hightower, J. Cell Physiol. 128, 239 (1986), and as components of some steroid binding receptors. E. Baulieu and M. Catelli, Alan. R. Liss, Inc., New York, 275 (1989). These proteins also appear to act as antigens in anti-bacterial, D. Young et al., Proc. Natl. Acad. Sci. USA 85, 4267 (1988); A. Mehlert et al., Biochem. Soc. Trans. 16, 721 (1988), and autoimmune reactions. S. Minota et al., J. Exp. Med. 168, 1475 (1988), S. Minota et al., J. Clin. Invest. 81, 106 (1988). Several other functions have been suggested as well. See S. Lindquist, Ann. Rev. Biochem 55, 1151 (1986), M. Schlesinger et al., Cold Spring Harbor Laboratory, 1982, M. Pardue et al., Alan R. Liss, Inc. (1989), M. Schlesinger, J. Cell Biol. 103, 321 (1986), E. Craig, CRC Critical Reviews in Biochemistry, Vol. 18, no. 3, 239 (1985).
The inducible forms of hsps are elicited by a variety of stressors, including elevated temperature, M. Schlesinger et al., Cold Spring Harbor Laboratory, 1982, heavy metals, M. Schlesinger et al., Alan R. Liss, Inc., 137 (1989), amino acid analogs, P. Kelley and M. Schlesinger, Cell 15, 1277 (1978), L. Hightower, J. Cell. Physiol. 102, 407 (1980), oxidative radicals, M. Ashburner, Chromosoma 31, 356 (1970), J. Compton and B. McCarthy, Cell 14, 191 (1978) ischemia or return from anoxia, S. Guttman, Cell 22, 299 (1980), M. Ashburner and J. Bonner, Cell 17, 241 (1979), mechanical trauma, L. Hightower and F. White, Cold Spring Harbor Laboratory, 369 (1982), D. Gower et al., J. Cell Biol. 103, 291 (1986), and abnormal proteins. J. Ananthan et al., Science 232, 522 (1986). The unifying functional characteristic is that they act to maintain normal cellular function under non-ideal conditions.
The functional importance of hsps to cells under stress extends to the arterial wall and atherosclerosis. The developing plaque involves histological and biochemical changes in the composition of the arterial wall, R. Ross, N. Eng. J. Med. 314, 488 (1986). In chronically stressed atherosclerotic plaque cells, hsp alterations may have serious implications. As an example, one general effect of hsps is to stabilize membranes of cells, R. Shiver et al., Eur. J. Cell Biol. 46, 181 (1988), and it has been suggested that stabilization of arterial lysosomal membranes may facilitate plaque cells to entrap lipids, J. Berthet et al., Biochem. J. 59, 182 (1951), C. deDuve, Harvey Lectures 59, 49 (1965), P. Berberian et al., Fed. Proc. 43, 711 (1984). Cell stabilization by hsps additionally may help to determine the relative survival of cells within various regions of the developing plaque, while its relative deficiency may define areas vulnerable to necrosis.
There is evidence that hsps can be exchanged between cells. L. Hightower and P. Guidon, J. Cell. Physiol. 138, 257 (1989), M. Tytell et al., Brain Res. 363, 161 (1986). Thus, it is possible that hsps' effects may not be limited to the stressed cell synthesizing them. However, no one has tested the effect of exogenously added hsps on cell survival. The present invention is based on our findings after undertaking such tests.